Complement activation and the production of inflammatory mediators during the treatment of severe sepsis in humans.

Sepsis or septic shock is frequently associated with activation of the complement system, coagulation and fibrinolytic changes and the release of several cytokines. In this study we analyzed the relation of complement activation to the inflammatory mediators, hemodynamic and biochemical parameters and severity of illness and outcome in 20 consecutive patients with clinically defined sepsis. Levels of C3a and C3d were elevated in 90% of the patients (median levels 0.19 mg/l and 8.6 mg/l respectively) in comparison to 14% and 42%, respectively of 7 patients with non-septic shock. Levels of C4 were decreased in only 1 of the 20 septic patients. Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, respectively (median levels 122 ng/l and 1300 U/ml) and were clearly interrelated (r = 0.67, p less than 0.01). C3a levels correlated with the APACHE II score (r = 0.57, p less than 0.05) and high C3a levels were associated with fatal outcome (p less than 0.05). C3a was also correlated inversely with mean arterial pressure (r = 0.50, p less than 0.01). Levels of complement C3a and C3d significantly correlated with levels of plasminogen activator inhibitor-1 (PAI) and correlated inversely with AT-III levels. We found no correlation between these complement products and leukocyte counts or lactate levels, nor was there a correlation between C3a or C3d and the cytokines TNF and IL-6. Levels of C3a and C3d did not decrease significantly during the first 24 h of treatment, in contrast to a clear decrease in IL-6 levels in all patients and a decrease in TNF in the surviving patients. TNF levels remained stable or increased in the non-survivors. We conclude that both the complement system and the cytokine system are involved in the pathogenesis of septic shock and may be involved in the development of some of the fatal complications like hypotension and disseminated intravascular coagulation.     

Diabetes and Autonomic Neuropathy: An Immunological Association?

Lymphocytic infiltration of autonomic ganglia found at autopsy and a strong clinical association with iritis suggests that diabetic autonomic neuropathy might have an immunological basis. We measured levels of circulating immune complexes, complement (C3, C4), complement breakdown products (C3d), and insulin antibodies in diabetics with autonomic neuropathy and a history of iritis (n = 17), compared to diabetics of similar age and duration with autonomic neuropathy but no history of iritis (n = 20), and with uncomplicated insulin-dependent diabetics (n = 23), together with normal controls (n = 26). We found higher levels of circulating immune complexes in patients with autonomic neuropathy (irrespective of iritis) compared to normal controls, and differences in C3d levels suggesting complement activation. C4 levels were unexpectedly normal in the diabetics with autonomic neuropathy, in contrast to the uncomplicated insulin-dependent diabetic controls. Insulin antibody levels showed no difference between the three groups of diabetics. These findings suggest that immunological mechanisms may be implicated in the aetiology of diabetic autonomic neuropathy and that further studies are indicated.     

Effects of alendronate on bone mass in patients with primary biliary cirrhosis and osteoporosis: Preliminary results after one year

Detailed complement system studies were performed in 22 patients with adult coeliac disease. Activation products of C3 were observed in the fresh sera of all untreated patients, while only 4 had activation products of factor B of the alternate pathway. Levels of C4 and C3 were lower than normal mean, but only the depression of C4 reached a level of statistical significance. The amounts of circulating C3 activation products were significantly reduced when the patients were on a gluten-free diet. There is thus evidence that activation of the classical pathway of the complement system takes place in adult coeliac disease, and there is an association between gluten ingestion and the complement activity. We suggest that a possible mechanism of tissue injury in this disease is activation of complement factors by a humoral immune reaction to dietary gluten in the intestinal wall.     

Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(- )-inhibitor complexes in sepsis

Considerable evidence indicates that activation of the contact system of intrinsic coagulation plays a role in the pathogenesis of septic shock. To monitor contact activation in patients with sepsis, we developed highly sensitive radioimmunoassays (RIAs) for factor XIIa-Cl(- )-inhibitor (Cl(-)-Inh) and kallikrein-Cl(-)-Inh complexes using a monoclonal antibody (MoAb Kok 12) that binds to a neodeterminant exposed on both complexed and cleaved Cl(-)-Inh. Plasma samples were serially collected from 48 patients admitted to the intensive care unit because of severe sepsis. Forty percent of patients on at least one occasion had increased levels of plasma factor XIIa-Cl(-)-Inh (greater than 5 x 10(-4) U/mL) and kallikrein-Cl(-)-Inh (greater than 25 x 10(- 4) U/mL), that correlated at a molar ratio of approximately 1:3. Levels of factor XII antigen in plasma and both the highest as well as the levels on admission of plasma factor XIIa-Cl(-)-Inh in 23 patients with septic shock were lower than in 25 normotensive patients (P = .015: factor XII on admission; P = .04: highest factor XIIa-Cl(-)-Inh; P = .01: factor XIIa-Cl(-)-Inh on admission). No significant differences in plasma kallikrein-Cl(-)-Inh or prekallikrein antigen were found between these patients' groups. Elevated Cl(-)-Inh complex levels were measured less frequently in serial samples from patients with septic shock than in those from patients without shock (P less than .0001). Based on these results, we conclude that plasma Cl(-)-Inh complex levels during sepsis may not properly reflect the extent of contact activation.     

Kupffer cell complement receptor clearance function and host defense

Kupffer cells are well known to be important for normal host defense function. The development of methods to evaluate the in vivo function of specific receptors on Kupffer cells has made it possible to assess the role of these receptors in host defense. The rationale for studying complement receptors is based on the proposed important role of these receptors in host defense and on the observation that the hereditary deficiency of a complement receptor is associated with recurrent severe bacterial infections. The studies reviewed here demonstrate that forms of injury that are associated with depressed host defense including thermal injury, hemorrhagic shock, trauma, and surgery also cause a decrease in complement receptor clearance function. This decrease in Kupffer cell receptor clearance function was shown not to be the result of depressed hepatic blood flow or depletion of complement components. Complement receptor function was also depressed following the phagocytosis of particulates that are known to depress Kupffer cell host defense function. Endotoxemia and bacteremia also were associated with a depression of complement receptor function. Complement receptor function was experimentally depressed in uninjured animals by the phagocytosis of IgG-coated erythrocytes. There was a close association between the depression of complement receptor clearance function and increased susceptibility to the lethal effects of endotoxin and bacterial infection. These studies support the hypotheses that complement receptors on Kupffer cells are important for normal host defense and that depression of the function of these receptors impairs host defense.     

Evidence for activation of the alternate complement pathway in patients with juvenile rheumatoid arthritis

OBJECTIVE: Complement activation has been shown to occur in patients with juvenile rheumatoid arthritis (JRA). Since the two pathways of complement are activated by different stimuli (the alternate pathway by microbial products and IgA, and the classical pathway by immune complexes), we decided to study the relative contribution of the two pathways of complement activation in patients with JRA. METHODS: In 56 patients with JRA, plasma levels of C3 and C4 were measured by turbidimetric assays, and those of C4d, factor Bb and sC5-9 complex by solid-phase enzyme immunoassays. Levels beyond the mean +/- 2 S.D. of normal were considered abnormal. RESULTS: Plasma C3 and C4 levels were decreased in one patient each. The C4d values were increased in 17 patients, whereas levels of factor Bb were elevated in 42 patients and levels of sC5-9 complex were elevated in 51 patients. The values of factor Bb and sC5-9 had a linear correlation (r = 0.75), but there was no significant correlation between C4d and sC5-9 levels (r = 0.36). CONCLUSION: Complement activation in JRA is initiated predominantly by the alternate pathway and culminates in the formation of terminal membrane attack complex.     

Endotoxin, prekallikrein, complement and systemic vascular resistance. Sequential measurements in man.

Eighteen patients were studied prior to and again within 6 hours after transurethral resection or cystoscopy. In addition to hemodynamic measurements, detection of endotoxin by limulus assay and bacteriologic sampling; prekallikrein, C3, C3 proactivator and lysosomal enzyme levels were measured. In five patients limulus assays were positive, and in one, gram-positive bacteremia developed but limulus assay remained negative. All six had significant decreases in prekallikrein, C3 or C3 proactivator. Systemic vascular resistance fell in all six. Four additional patients who had a decrease in systemic vascular resistance were not endotoxemic or bacteremic; one of these had a decrease in prekallikrein only. In the remaining eight patients with neither bacteremia nor endotoxemia, systemic vascular resistance did not change or increase after instrumentation. One had a decrease in C3 proactivator, another in prekallikrein. There was no significant difference in age, disease, antibiotic therapy or bactermia in the two groups of patients. Four of the five resectional procedures were performed in the group that showed decreases in systemic vascular resistance. The data suggest that acute endotoxemia or gram-positive bacteremia in man is associated with depletion of prekallikrein, decreased peripheral resistance and, in some instances, activation of the complement system.     

Activation of the contact system in insect-sting anaphylaxis: association with the development of angioedema and shock

A postulated role of the contact system in anaphylactic reactions to insect stings was investigated. During prospective, in-hospital sting challenge, we collected serial blood samples from five normal volunteers and 16 patients with a history of insect-sting anaphylaxis. Activation of the contact system was assessed by measuring plasma levels of factor XIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes as well as those of cleaved high molecular weight kininogen (HK). In addition, antigenic levels of (pre)kallikrein, factor XII, and HK were measured. No significant changes in contact system parameters were observed in any of the five volunteers or the four patients who did not develop an anaphylactic reaction after sting challenge. In contrast, significant changes in contact system parameters occurred in 7 of the 12 patients with anaphylactic symptoms after challenge. Peak levels of either C1-inhibitor complex were found 5 minutes after the onset of anaphylactic symptoms. The increase in C1-inhibitor was most pronounced in the 4 patients with angioedema, 2 of which also developed shock. However, activation of HK was observed in all four patients with angioedema, the two patients with shock but no angioedema, as well as in 1 of the remaining 6 patients with anaphylactic symptoms other than angioedema or shock. Thus, activation products of the contact system may be involved in the pathogenesis of angioedema and shock in insect- sting anaphylaxis.     

Complement activation induced by ischemia-reperfusion in humans: a study in patients undergoing partial hepatectomy

BACKGROUND/AIM: Activation of the complement system is induced by ischemia-reperfusion (I/R) in animal models. Whether I/R also induces complement activation in humans is not known. Here, we investigated complement activation in patients undergoing major liver resection. METHODS: In 11 of 17 patients, the hepatoduodenal ligament was clamped, making the liver transiently ischemic (HEMI+; mean ischemia time, 42 +/- 18 min); 6 patients were operated without clamping (HEMI-). Activation at plasma level (circulating activation products) was studied in blood samples collected prior to surgery and 5, 24 and 48 h thereafter. Parameters analyzed were C4b/c and C3b/c, C4d and C3d, C3a, as well as complexes between complement and C-reactive protein (CRP), which reflect CRP-induced complement activation. Activation at tissue level (C3 and C4 fixation) was studied in liver biopsies obtained before and after resection. RESULTS: In plasma, post-operative levels of C4b/c and C3b/c were not different from baseline levels in both groups. Mean plasma levels of C4b/c and C3b/c were significantly decreased at 24 h post-surgery in the HEMI+ group (p=0.02 and p=0.07). At the same time, levels of C4d-CRP and C3d-CRP were significantly increased (p<0.01 for both parameters). At tissue level, activated complement fragments were observed intracellularly in some pericentral hepatocytes. In I/R livers, large numbers of hepatocytes were positively stained for all complement activation products. CONCLUSIONS: Our data show that in situ complement activation via the classical route occurred during liver resection and that ischemia and/or reperfusion may have contributed to activation. Levels of complement activation products in the circulation were low, showing that transient ischemia had no severe influence on systemic complement activation, suggesting a locally contained response.     

Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections

The complement system is an essential element in our innate defense against infections with Neisseria meningitidis. We describe 2 cases of meningococcal septic shock, 1 of them fatal, in 2 children of a Turkish family. In the surviving patient, alternative pathway activation was absent and factor D plasma concentrations were undetectable. Concentrations of mannose-binding lectin (MBL), C1q, C4 and C3, factor B, properdin, factor H, and factor I were normal. Mutation analysis of the factor D gene revealed a T638 > G (Val213 > Gly) and a T640 > C (Cys214 > Arg) mutation in the genomic DNA from the patient, both in homozygous form. The consanguineous parents and an unaffected sister had these mutations in heterozygous form. In vitro incubation of factor-D-deficient plasma of the boy with serogroup B N meningitidis showed normal MBL-mediated complement activation but no formation of the alternative pathway C3-convertase C3bBbP, and severely decreased C3bc formation and terminal complement activation. The defect was restored after supplementation with factor D. In conclusion, this is the second report of a factor D gene mutation leading to factor D deficiency in a family with meningococcal disease. This deficiency abolishes alternative-pathway dependent complement activation by N meningitidis, and leads to an increased susceptibility to invasive meningococcal disease.     

Serologic diagnosis of access device-related staphylococcal bacteremia.

Staphylococcal bacteremia occurs frequently in patients undergoing long-term hemodialysis (dialysis patients). Although such bacteremia is frequently uncomplicated, it may be associated with endocarditis, metastatic infection or suppuration at the access site requiring excision of the access device for control of the infection (complicated bacteremia). To distinguish patients with uncomplicated bacteremia from those with complications, we measured staphylococcal teichoic acid antibodies by agar-gel diffusion and immunoglobulin G (IgG) antibodies by radioimmunoassay in 18 patients with staphylococcal bacteremia undergoing long-term hemodialysis. Although teichoic acid antibodies were not detected in five patients with uncomplicated bacteremia, they were observed in only three of 13 patients with complicated bacteremia. IgG staphylococcal antibodies were present in 10 of 13 patients with complicated bacteremia compared to none of five patients with uncomplicated bacteremia compared to none of five patients with uncomplicated bacteremia (p less than 0.05). Thus, radioimmunoassay was spuerior to agar-gel diffusion in identifying dialysis patients with complicated bacteremia. In patients with increased concentrations of IgG staphylococcal antibodies by radioimmunoassay, the diagnosis of endocarditis, metastatic infection and suppuration at the access site should be considered. Prolonged antibiotic therapy and/or operative removal of the access device may be necessary.     

The role of complement in glucan-induced protection against septic shock

Previous studies from our laboratory have shown that glucan will significantly enhance survival, decrease bacteremia, maintain reticuloendothelial function, and reduce histopathology in a murine model of gram-negative septic shock [1]. The present study was undertaken to evaluate the role of complement in glucan-enhanced protection against septic shock. AKR/J mice, which are congenitally C5-deficient, and ICR/HSD mice that were complement-depleted by treatment with purified cobra venom factor (CVF), were injected IP with glucan (50 mg/kg) on days 5 and 3 prior to IP challenge with 1 X 10(8) E. coli. Survival data indicated that glucan (p less than 0.05) increased survival in both C5-deficient and complement-depleted mice. Glucan prophylaxis resulted in a neutrophilic leukocytosis 8 h following E. coli challenge. However, glucan did not alter bone marrow proliferation. We conclude that, 1) glucan's protective effect on survival is not dependent on complement, 2) complement is not required for glucan-induced neutrophilic leukocytosis in this model, and 3) glucan does not enhance bone marrow proliferation in complement-deficient mice.     

Kallikrein-kinin system activation in streptococcal toxic shock syndrome.

A retrospective analysis of 7 patients with streptococcal toxic shock revealed isolated prolongation of the activated partial thromboplastin time, which returned to normal during recovery. Levels of factor XII were reduced in 2 patients who had single factor assays performed, consistent with activation of the kallikrein-kinin system. We speculate that bradykinin release following activation of the kallikrein-kinin system in streptococcal toxic shock may underlie the features of pain, capillary leaking, and severe hypotension characteristic of this syndrome.     

The alternative pathway of complement in sheep during the course of infection with Trypanosoma congolense and after Berenil treatment

Experimental T. congolense infections in sheep resulted in a striking decrease in parameters of the alternative complement pathway (ACP), ie. factor B, C3 and haemolytic complement activity (HA) initiated via the ACP. The levels of factor B, C3 and HA declined before, during and after the first wave of parasitemia which reached a peak at day 8. Levels of 20 to 25% of normal values (factor B) and 20% (C3, HA) persisted throughout the course of the infection. After Berenil treatment, when no parasites were detected in blood, their serum levels remained low. The returned to normal values about 8 (factor B) to 20 days (C3, HA) after trypanocidal treatment. Serum concentrations of factor B were significantly elevated in some, but not all sheep 6 days after infection with T. congolense. The sheep were tested for their potential state of immuno-modulation by immunization with Brucella abortus 4 days after trypanocidal treatment. In contrast to other sheep, the sheep which had shown early elevated serum factor B levels were found to express immune enhancement. It is suggested that there might be a positive correlation between the degree of enhanced serum levels of factor B at the early stage of infection and enhanced immune responsiveness.     

Cardiovascular function and arterial blood gases during sham dialysis in healthy man

Cardiovascular function and alveolar gas exchange were studied in healthy subjects undergoing sham dialysis (SHD)--i.e. the circulation of blood through a cuprophane dialyzer with the dialysate compartment closed to avoid diffusion and convective transport of fluid and solutes. The blood-membrane contact induced complement activation (rise in C3d) and transient leukopenia, as described during clinical hemodialysis. PaO2, PaCO2 and calculated oxygen uptake remained unchanged. Heart rate, cardiac index (thermodilution), systemic vascular resistance index and brachial and pulmonary arterial blood pressures did not change significantly during 150 min of SHD (n = 8). In 12 subjects, in whom more frequent measurements were made during the first 30 min of SHD, pulmonary arterial systolic and diastolic blood pressures decreased significantly while the dialyzer and the tubing set filled with blood, and pulmonary arterial mean blood pressure did not change significantly. Pulmonary capillary wedge pressure fell during the filling phase, but did not change significantly during SHD; pulmonary vascular resistance index remained unchanged. We conclude that in nonuremic subjects sham dialysis with a cuprophane dialyzer does not result in hypoxemia, pulmonary vascular constriction and pulmonary hypertension, in spite of complement activation and marked leukopenia.     

Hypocomplementemia during tocilizumab treatment: Long-term follow-up results

Hypocomplementemia has been reported in patients with rheumatoid arthritis treated with tocilizumab (TCZ), but its long-term consequences are unknown. We assessed the long-term outcome of patients treated with TCZ who developed hypocomplementemia regarding serious bacterial infections or autoimmune diseases (AID).The charts of patients treated with TCZ at two rheumatology centers were reviewed retrospectively. Data regarding patients’ age, gender, disease duration, autoantibodies status, previous or concomitant treatments, blood counts, liver enzymes, C3 and C4 levels at baseline and during TCZ treatment, episodes of infections, allergic reactions, and AID were analyzed. Univariate analysis was used to compare patients with low C3, C4 levels versus patients with normal C3, C4 levels. Variables that were statistically significant associated or tended to be associated with low C3 or C4 were included in multiple variable logistic regression.Of 132 patients treated with TCZ, 108 had serial measurements of serum complement concentration. Thirty-three (30%) patients developed low C4 levels and 23 (21%) had also low C3. Mean TCZ treatment period was 4.9 years (range, 1–14 years). All patients had normal complement levels at baseline. Leukopenia occurred in 18 (16.7%) patients, 14 of whom (77%) had low complement. Persistent leukopenia was observed in 8% and 5.3% of patients with normal C3 and C4 levels, respectively, as opposed to 47% and 42% of patients with low C3 or low C4, respectively. Low C3, C4 levels correlated with prolonged TCZ treatment retention time and effectiveness. There were no serious bacterial infections or new onset AID.Hypocomplementemia during TCZ treatment was accompanied by leukopenia that correlated with treatment duration. Hypocomplementemia was not associated with serious bacterial infections or new onset AID. Decreased complement levels were associated with treatment longevity. The role of monitoring complement level in predicting treatment response or assessing disease activity deserves further investigation.     

Bronchoalveolar lavage fluid and serum complement activity in pulmonary sarcoidosis

In this work, using bronchoalveolar lavage fluids (BALF), we demonstrated the presence of complement within airways by assaying hemolytic activity of the whole classical pathway (CH50) and by measuring the complement component C2 (C2H50). Patients with sarcoidosis, patients with idiopathic pulmonary fibrosis (IPF), and healthy control subjects were compared. No CH50 activity was found in BALF from healthy control subjects (n = 9), but some activity (mean, 20 CH50) was associated with IPF (n = 7). Complement activities ranged from 40 to 554 CH50 in patients with sarcoidosis (n = 27). During the treatment, complement activity decreased in BALF from the few patients in our series who received corticotherapy. C2 hemolytic activity was detected in BALF from the normal control group (in the absence of CH50 activity). In the sarcoidosis and IPF groups when CH50 was present, the variations in the C2/CH50 ratio were studied. The high ratio observed in BALF from patients with sarcoidosis and a chronic derangement of alveolar structure suggests either an increased C2 production or an alternative complement pathway (C2-independent) activation within their lungs.     

The role of complement,immunoglobulin and bacterial antigen in coagulase-negative staphylococcal shunt nephritis

We describe three patients with arrested hydrocephalus in whom glomerulonephritis developed secondary to Staphylococcus epidermidis bacteremia from an infected ventriculoatrial shunt. Investigation of the immune-mediated renal disease associated with this chronic infection showed that (1) complement depletion during the acute phase of bacteremia and nephritis was predominantly via the classic pathway; (2) rheumatoid factor was associated with bacteremia, fever, proteinuria and low complement levels; (3) early complement components (C1q, C4, C3), immunoglobulin (predominantly immunoglobulin M [IgM]), Staph. epidermidis antigen(s) and electron dense subendothelial deposits were localized within the renal glomerulus; (4) C1q and IgM derived from patient serums, were the most prominent in vitro immunoreactants to Staph. epidermidis cell walls; and (5) the causative organisms, Staph. epidermidis, shared common antigens with Staph. aureus, and antibody from patient serums cross reacted with extracts from both of these organisms.     

Hypocomplementemia in rheumatoid arthritis

Over a two and a half year period, we saw 16 patients with classic rheumatoid arthritis and serum complement values below normal. In addition to severe joint involvement, high rheumatoid factor titers and increased immunoglobulin M (IgM) values, extra-articular manifestations were particularly prominent. There was an unusually high incidence of recurrent serious bacterial infections during the period of observation. Complement values were lowest during subacute exacerbations of the joint disease or development of extra-articular complications. Studies of individual components of complement revealed low values for C4 (all of 14 tested) and C2 (six of 12 tested). Other components were mostly normal. Anticomplementary activity could be demonstrated in several hypocomplementemic serums. Rheumatoid factor and IgM (both 19S and 7S) levels were highest when whole complement was lowest. Fourteen serums produced precipitin bands against heat-aggregated immunoglobulin G (IgG).The low levels of whole hemolytic complement (CH₅₀) and the presence of complement-fixing material in these serums suggest utilization of complement by immune complexes. The pattern of decreased C4 and C2 with more normal amounts of other components implies complement activation via C1. The concurrence of hypocomplementemia with exacerbations and complications of rheumatoid arthritis suggests that complement-fixing immune complexes may contribute to these events. In addition, the frequent infections may mean that these immunologic abnormalities lead to impaired host resistance to infection.     

Fibrinolysis in normal plasma and blood: evidence for significant mechanisms independent of the plasminogen-plasmin system.

Fibrinolytic activity of normal plasma and blood has been measured by 125l-fibrin solid phase assay. Activity of plasma is not affected by removal of plasminogenplasmin by affinity chromatography. Activities of euglobulin and pseudoglobulin fractions are approximately equal. epsilon-aminocaproic acid (EACA) (10 mM), tranexamic acid (10 mM), diisopropylfluorophosphate (DFP, 50 mM), and soybean and lima bean trypsin inhibitors (100 mug/ml) do not inhibit plasma activity at concentrations that inhibit pure plasmin and urokinase-activated plasma. Activity is not affected by glass contact and is not inhibited by inhibitors of contact or enzymatic activation of Hageman factor (hexadimethrine bromide, 100 mug/ml; cytochrome C, 250 mug/ml; spermidine, 2 mM; phenylmethylsulfonylfluoride, 1 mM). It is inhibited partially (30%-40%) by heating (56 degrees C, 30 min) and by zymosan (2.5 mg/ml; 40%-90% inhibition), and is increased by hydrazine (20 mM), salicylaldoxime (20 mM), DFP (50 mM), and tosyl-L-arginine methyl ester (TAMe, 10 mM)-the latter two at concentrations known to inhibit Cls of the classic, and factor D of the alternate complement pathways. Increase fibrinolytic activity with TAMe is associated with reciprocal decrease in classic and alternate complement pathway activity. It is concluded that normal plasma fibrinolytic activity is relatively independent of plasmin as the ultimate fibrinolytic enzyme, that Hageman factor-dependent pathways are of minor importance, and that significant heat-stable and heat-labile nonplasmin fibrinolytic activities are operative. These may include proteinases involved in complement activation, and in common control of classic and alternate complement pathways, as well as other nonplasmin proteinases.